Browsing by Subject "Mesangial matrix"

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    Differential role of mesangial cells and podocytes in TGF-ß-induced mesangial matrix synthesis in chronic glomerular disease
    (Murcia : F. Hernández, 2009) Lee, Hyun Soon; Song, Chi Young
    Glomerulosclerosis is characterized by mesangial matrix accumulation that is mediated primarily by activation of transforming growth factor-ß (TGF-ß). Unlike podocytes, mesangial cells secrete TGF-ß in response to common in vitro fibrogenic stimuli. However, mesangial immunostaining for active TGF-ß1 in chronic glomerular disease is almost negligible, despite increased mesangial TGF-ß1 mRNA expression, while podocytes covering the sclerotic glomerular segments exhibit increased TGF-ß1 protein expression. The mechanisms whereby TGF-ß is activated in the diseased glomeruli and how the activated TGF-ß leads to mesangial matrix overproduction are not clear. We provide evidence that TGF-ß secreted as latent complexes by mesangial cells is stored in the mesangial matrix, from which soluble forms of latent TGF-ß are released and localized to the podocyte surface in chronic glomerular disease. Podocyte-derived reactive oxygen species, plasmin and thrombospondin-1, particularly renin-angiotensin-aldosterone system-induced oxidative stress, seem to be involved in TGF-ß activation in podocytes. We also provide evidence that the TGF-ß- induced secretion of connective tissue growth factor and vascular endothelial growth factor by podocytes acts as a paracrine regulatory mechanism on mesangial cells, which may cause mesangial matrix accumulation culminating in the development of glomerulosclerosis. Collectively, these data bring new insights into our understanding of the roles of the mesangial cells and podocytes in the TGF-ß-induced mesangial matrix synthesis in chronic glomerular disease.
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    Paracrine role for TGF-ß-induced CTGF and VEGF in mesangial matrix expansion in progressive glomerular disease
    (F. Hernández y Juan F. Madrid. Universidad de Murcia. Departamento de Biología Celular e Histología, 2012) Soon Lee, Hyun
    Transforming growth factor-ß (TGF-ß) is a key regulator of extracellular matrix (ECM), and may mediate the development of glomerulosclerosis with accumulation of mesangial matrix. Mesangial cells secrete TGF-ß in response to common in vitro fibrogenic stimuli. Yet mesangial immunostaining for active TGF-ß1 is frequently negative in chronic glomerular disease. TGF-ß is rather expressed and/or activated by podocytes in both mesangial and podocyte diseases. Activated TGF-ß/Smad signaling by podocytes may induce connective tissue growth factor (CTGF or CCN2) and vascular endothelial growth factor (VEGF) expression. Podocyte CTGF seems to have paracrine effects on mesangial cells to stimulate CTGF expression. CTGF appears to stimulate the fibronectin-matrix assembly via enhanced cell-surface expression of α5ß1 integrin in the mesangium of diseased glomeruli. Podocyte VEGF-A overexpression also seems to play a paracrine role on mesangial cells to upregulate VEGF/VEGF receptor systems and to overproduce matrix proteins. Thus, paracrine CTGF and VEGF may contribute to mesangial matrix accumulation in chronic glomerular disease, culminating in the development of glomerulosclerosis. Together, these data bring new mechanistic insights into our understanding of the pathogenic role of TGF-ß-induced CTGF and VEGF in mesangial matrix expansion in chronic progressive glomerular disease